Numerous therapeutic agents exist as crystalline salts, in which a relatively basic site on the drug molecule is protonated and accompanied by a nearby counterion of negative charge. Such salts typically have significant advantages in solubility and bioavailability over the neutral crystalline API forms. However, if the pKa of the API basic site is too low, there is a risk that over long term storage of the tablets, disproportionation, or proton transfer, can occur when the API salt is formulated with standard oral tablet dosage form excipients with basic sites such as magnesium stearate and croscarmellose sodium. Such disproportionation leads to formation of the neutral free base form of the drug which can significantly reduce the bioavailability of the drug and thus dramatically impact the quality of the formulated drug product.
This invention describes the inclusion of pharmaceutically acceptable organic acid compounds, such as maleic and tartaric acids, into pharmaceutical formulations of API salts with relatively low pKa's that are prone to disproportionation. Inclusion of acid compounds, such as maleic and tartaric acids, at relatively low weight percentage in tablets is expected to significantly reduce overall amount of form conversion caused by proton transfer mediated disproportionation. In addition, the inclusion of acid compounds, such as maleic and tartaric acids, are expected to allow for the use of certain excipients known to promote disproportionation such as magnesium stearate, sodium stearyl fumarate, and/or croscarmellose sodium which have critical functionalities in many tablet formulations. Thus, the invention will allow for more robust and effective oral tablet formulations of low pKa API salts.